Asymmetric synthesis of anti-(2S,3S)- and syn-(2R,3S)-diaminobutanoic acid

Conjugate addition of homochiral lithium N-benzyl-N-alpha-methylbenzylamide to tert-butyl (E)-cinnamate or tert-butyl (E)-crotonate and in situ amination with trisyl azide results in the exclusive formation of the corresponding 2-diazo-3-amino esters in > 95% de. Amination of the lithium (E)-enolates of tert-butyl (3S, alphaR)-3-N-benzyl- N- amethylbenzylamino- 3-phenylpropanoate or tert-butyl (3S, alphaS)-3-N-benzyl-N-alpha-methylbenzylaminobutanoate with trisyl azide gives the (2R, 3R, alphaR)- and (2S, 3S, alphaS)-anti-2-azido-3-amino esters in good yields and in 85% de and > 95% de respectively. Alternatively, tert-butyl anti-(2S, 3S, alphaS)-2-hydroxy-3-N-benzyl- N-alpha-methylbenzylaminobutanoate may be converted selectively to tert-butyl anti-(2S, 3S, alphaS)-2-azido-3-N-benzyl-N-alpha-methylbenzylaminobutanoate by aziridinium ion formation and regioselective opening with azide. Deprotection of tert-butyl (2S, 3S, alphaS)-2-azido-3-aminobutanoate via Staudinger reduction, hydrogenolysis and ester hydrolysis furnishes anti-(2S, 3S)-diaminobutanoic acid in 98% de and 98% ee. The asymmetric synthesis of the diastereomeric syn-(2R, 3S)-diaminobutanoic acid ( 98% de and 98% ee) was accomplished via functional group manipulation of tert-butyl anti-( 2S, 3S, alphaS)- 2-hydroxy- 3-N-benzyl-N-alpha-methylbenzylaminobutanoate in a protocol involving azide inversion of tert-butyl (2S, 3S)2- mesyloxy-3-N-Boc-butanoate and subsequent deprotection.